Treatment of type i diabetes mellitus

ABSTRACT

Use of a growth hormone antagonist to reduce the overnight insulin requirement of a patient suffering from Type I diabetes mellitus or from dawn phenomenon.

Diabetes mellitus is a chronic metabolic disorder, which is broughtabout by either insulin deficiency or insulin resistance. Diabetesmellitus is a disease characterised by physiologic and anatomicabnormalities in many organs, due to vascular abnormalities. However,the most prominent feature of the disease is disturbed glucosemetabolism, resulting in hyperglycaemia Diabetes mellitus is usuallydivided into two major categories: insulin-dependent diabetes mellitus(Type I diabetes), which usually develops in childhood or adolescenceand these patients are prone to ketosis and acidosis. The secondcategory of patients (Type II diabetes) are not insulin dependent andusually manage with diet and oral hypoglycaemic therapy. The annualincidence of Type I diabetes ranges from 10 cases/100000 persons fornon-white males to 16 cases/100000 persons for white males in the UnitedStates, with equal incidence between males and females. The prevalenceof Type I diabetes for all ages in the United States population is 160cases/100000 persons, with a slightly earlier onset for females withpeak age of onset at 10-12 years than for males with peak age of onsetat 18 years. Genetic background plays a major role in the development ofthe disease, with 40% concordance for Type I diabetes exhibited byidentical twins and increased incidence among family members. Genesassociated with increased susceptibility to Type I diabetes reside nearthe major histocompatibility complex on chromosome 6, with more than 90%of persons with Type I diabetes featuring DR3 or DR4 haplotypes or both.Likewise, siblings sharing DR3 or DR4 haplotypes from both parents moreoften than random develop Type I diabetes.

The onset of symptoms in Type I diabetes is usually acute and frequentlyfollows an antecedent viral infection which might be the trigger to aprocess leading to destruction of the beta cells secondary to autoimmune insulitis. When beta cell destruction reaches the critical point,the patient's reduced insulin levels lead to hyperglycaemia with thetypical symptomatology of Type I diabetes. At diagnosis approximately70% of patients with Type I diabetes have antibodies to islet cellcytoplasm i.e. antigens or to components of the islet cell surface.Approximately 15% of patients with Type I diabetes may also show otherauto immune features, such as hypothyroidism, Graves' disease, Addison'sdisease, myasthenia gravis and pernicious anaemia. Autopsies of caseswith Type I diabetes show a typical lymphocytic infiltration in thepancreatic islets.

Treatment of Type I diabetes at present is not satisfactory and thedisease leads to serious life-threatening complications that can be onlypartly overcome with adequate control of insulin levels, which isusually difficult to accomplish in patients with juvenile onset. Inaddition to the acute diabetic syndrome, chronic manifestations lead tosevere arteriosclerosis with microadenopathy affecting the eye withpossible early blindness. One in 20 of all Type I diabetes patientsbecomes blind; about 40% of Type I diabetes develop renal failure,resulting in chronic hemodialisis and/or the need for renaltransplantation (4-7). Severe neuropathic changes are also typical forType I diabetes with many functional disorders associated with sensory,sympathetic and parasympathetic nerves. Cranial nerve, as well asperipheral nerve, may be involved. Treatment of neuropathy remainsunsatisfactory, despite normal control of glucose levels with adequateinsulin therapy.

Strokes are twice as frequent, myocardial infarctions are 2-5 times asfrequent and cardiovascular accidents are 5-10 times more frequent inpatients with Type I diabetes than among non-diabetic counterparts. Theprognosis of patients with Type I diabetes who survive acute myocardialinfarction is 3 times more grave compared to non-diabetics who surviveacute infarction and the same is true for other vascular complications.Severe and uncontrollable arteriosclerosis may also be associated with avariety of etiologies involving abnormalities in platelets, clottingfactors and lipid carriers, such as HGL levels, as well as uncontrolleddiabetes.

The main treatment regime for Type I diabetes involves parentaladministration of insulin, usually subcutaneously. Insulin is destroyedin the gastrointestinal tract. A common regime for Type I diabetespatients is to inject a combination of short and intermediate actinginsulins twice daily, before breakfast and before the evening meal. Moreintensive routines may involve multiple daily injections or continuoussubcutaneous infusion of soluble insulin. The more intensive regimestend to provide better control of blood glucose, however they are muchmore intrusive to the patient's life, which can be a particular problemwhen treating juveniles with this condition. Furthermore the intensivetreatment regimes are more expensive.

There are several side effects associated with treatment with insulin,the most important being hypoglycaemia. This is a common side effect,particularly of the more intensive treatment regimes, which can resultin severe morbidity and death. The symptoms include muscular weakness,incoordination, confusion and sweating. Severe hypoglycaemia can resultin coma. Other side effects include allergy to insulin which may producelocal or systemic reactions; loss or proliferation of fat at the sitesof injection; and, rebound hyperglycaemia. Rebound hyperglycaemiausually occurs after an unrecognised hypoglycaemic attack, for exampleduring sleep, and is caused by the release of counter-regulatoryhormones in response to insulin-induced hypoglycaemia.

A particular problem is the so-called “dawn phenomenon” in which theblood sugar level rises in the early hours of the morning. Until nowpatients who suffer from this have been obliged to take insulin duringthe night, or risk suffering from night-time hypoglycaemia.

In view of the unsatisfactory prognosis for patients with Type Idiabetes, and the side effects which may be experienced when usinginsulin to control the condition, it would be advantageous to have analternative treatment which could be used instead of, or in combinationwith insulin. The inventors have considered the use of a growth hormoneantagonist as a possible treatment for the condition.

Growth hormone (GH) is secreted by the anterior pituitary gland, underthe control of the hypothalamus. It not only regulates growth, but alsohas metabolic effects, increasing protein synthesis, stimulatinglipolysis, and increasing blood glucose. Its effects on carbohydratemetabolism are complex however. The somatogenic effects of GH areprimarily mediated by insulin like growth factor-1 (IGF-1).

Insulin dependent diabetes causes profound derangement in the GH/IGF-1axis. In poorly controlled Type I diabetics, GH levels are invariablyraised. The elevated GH levels are characterised by a greater pulseamplitude and higher baseline concentration of GH as compared to thelevels of normal subjects. Recent studies on the signal mode of GHindicate that it is the pulse amplitude rather than the increasedbaseline which lead to profound changes in insulin resistance indiabetic subjects (Pal et al., Diabetologia, in press). The high GHlevels lead to insulin resistance and aggravate the metabolicabnormalities of diabetes. GH excess has also been implicated in theaetiology of the dawn syndrome and may accelerate the development ofmicroangiopathy including proliferative retinopathy. Finally, anexcessive rise in beta hydroxy buturate (BOW) caused by raised GH hasbeen observed, particularly during puberty, and is compounded by theeffects of insulin waning overnight; this leads to the risk of rapiddecompensation with diabetic ketoacidosis in adolescents with diabetes.

Despite the elevated GH levels, IGF-I levels tend to be low in diabetesand this is related to decreased OH receptor function resulting from lowlevels of insulin (Holly J. M. P. et al., Clin Endocrinol, 29 (1988)667-675). The lower IGF-I levels in the presence of elevated GH levelshas been implicated in the slow growth and loss of adult height inchildren with diabetes (Salardi S. et al. Arch. Dis. Child, 62 (1987)57-62).

The mechanism underlying the increased GH levels has been the subject ofsome controversy. In the diabetic individual hyperglycaemia does notinhibit GH secretion as it does in healthy individuals and it has beenproposed that this reflects an altered hypothalamic function. Thisaltered hypothalamic function is characterised by reduced somatostatinlevels and resistance to the effects of somatostatin. Suppression ofplasma GH by somatostatin analogues and pirenzepine has led to reportedimprovement in metabolic control. However, this approach has provedinappropriate during childhood and adolescence when growth is rapid asit would inevitably lead to growth failure.

The inventors have surprisingly found that administration of a growthhormone antagonist has a beneficial effect in patients suffering fromType I diabetes mellitus, especially in combatting the “dawn phenomenon”referred to above by reducing the patient's overnight insulinrequirement.

The invention provides the use of growth hormone antagonists in thepreparation of pharmaceutical compositions to reduce the overnightinsulin requirement of a patient suffering from Type I diabetesmellitus. The pharmaceutical compositions of the invention may be usedto treat mammalian species, in particular, humans.

The growth hormone antagonist is preferably pegvisomant (SOMAVERT®).

Further provided by the invention is a method of treating Type Idiabetes mellitus comprising the step of administering insulin togetherwith a growth hormone antagonist to a patient suffering from Type Idiabetes mellitus during the evening in order to inhibit the dawnphenomenon. The patient may be a mammal, particularly a human.

The preferred growth hormone antagonist is pegvisomant (SOMAVERT®). Themethod of treatment preferably comprises administering between 1 mg and20 mg, more preferably between 5 mg and 10 mg of pegvisomant (SOMAVERT®)once daily.

The invention will now be described in more detail by way of an example.

Methods

7 adolescents of ages ranging from 1623, the average age being 18, HbA₁₂10.0% (7.2-10.8) were randomized in a crossover study comparingpegvisomant (SOMAVERT®) doses 5 mg and 10 mg once daily by subcutaneousinjection at 18.00 hours. At baseline and after each 3-week treatmentblock subjects were admitted for an overnight variable rate insulininfusion (target glucose 5 m/mol/L) and two-step (0.75 and 1.5ml⁵/Kg/min) hyperinsulinaemic euglycaemic clamp.

In more detail, prior to treatment and at the end of each treatmentblock, subjects underwent a fasted overnight (1800-0800 h) variable rateinsulin infusion for euglycaemia (5 mmol/l, achieved 0300-0800 h)followed by a 2 step (0.75 and 1.5 mU/kg/min) hyperinsulinaemiceuglycaemic clamp (0800-1200 h). Plasma insulin was measured every 30min,—hydroxybutyrate (OHB) and free fatty acids (FFA) every 60 min. Thestable isotopes ²H₂ glucose and ²Hs glycerol were infused during theclamp to determine glucose and glycerol turnover respectively.

Results

Data are expressed as mean (SEM) in the attached tables 1, 2 and 3. Inthe tables, * indicates p,0.05, **p 0.02 vs pre treatment values (P₀).IGF-I levels (ng/ml) fell with P₁₀: 154.8 28.1, ** vs P₀ 223.5 23.9.Overnight insulin requirements for euglycaemia (mU/kg/min) were reducedfollowing treatment: P₅ 0.25 0.01*, P₁₀ 0.24 0.02 ** vs P₀ 0.34 0.03,whereas plasma glucose and insulin levels did not change. Overnight FFA(mmol/l): P₁₀ 0.38 0.04* vs P₀ 0.51 0.04 and OHB (mmol/l): P₁₀ 0.150.02** vs P₀ 0.31 0.04 were significantly reduced by P₁₀ only. Therewere no changes in endogenous hepatic glucose production but glucosedisposal (mol/kg/min) fell during step 2 with P₅: 40.6 4.6* vs P₀ 48.54.2. Glycerol production (rate of appearance (Ra) (mol/kg/min) (n=5) wassurpressed by P₁₀ during step 2: P₁₀ 1.2 0.1* vs P₀ 2.0 0.3. Inconclusion, GH blockade with pegvisomant results in reduction inovernight insulin requirements, with reduced glycerol Ra, and GHblockade with pegvisomant (10 mg) results in reduction in FFA and OHB.Failure to observe corresponding changes in glucose turnover during thehyperinsulinaemic clamp may reflect reduction in circulating IGF-I.

Results of further tests are shown in Table 4, as follows:

IGF-1 levels (ngm/L) were reduced from 214.0 (26.4) to 207.1 (34.9)after 5 mg pegvisomant (SOMAVERT®) (P=0.7) and reduced to 144.2 (26.2)after 10 mg pegvisomant (SOMAVERT®) (P=0.01).

Overnight (03.00-08.00 hours) insulin requirements for euglycaemia(mU/Kg/min) were 0.35 (0.03) at baseline, 0.24 (0.04) after 5 mgpegvisomant (SOMAVERT®) (P=0.02) and 0.25 (0.04) after 10 mg pegvisomant(SOMAVERT®) (P=0.01).

Total body glucose disposal (m-value) was not altered during either stepof the hyperinsulinaemic clamp (08.00-12.00 hours) by either dose ofpegvisomant (SOMAVERT®). TABLE 1 Fasting Bloods (0800 h) Pre Treatment 5mg 10 mg IGF-I 223.5 183.8 154.6* (23.9) (38.1) (28.1) IGFBP-3 3018.32943.4 2689.6 (123.0) (298.2) (310.6)

TABLE 2 Overnight Steady State Period of Euglycaemia (0300-0800 h)Pre-Treatment 5 mg 10 mg Glucose 5.3 5.1 5.5 (mmol/l) (0.07) (0.04)(0.09) Insulin Requirement 0.34 0.25* 0.24** (mU/Kg/min) (0.03) (0.01)(0.02) Plasma Insulin 21.8 19.3 18.3 (mU/I) (2.4) (1.4) (1.6) MetabolicClearance Rate Insulin 14.1 14.2 12.7 (1.5) (1.1) (1.3) Non EssentialFatty Acid (NEFA) 0.51 0.52 0.38* (mmol/l) (0.04) (0.04) (0.04)β-Hydroxybutyrate 0.31 0.25 0.15** (0.04) (0.05) (0.02) IGFBP-1 44.356.6 53.0 (3.0) (3.7) (2.7)

TABLE 3 Hyperinsulinamic Clamp (0800-1200 h) Pre Treatment 5 mg 10 mgGlucose Step 1 4.9 5 4.9 (mmol/l) (0.02) (0.03) (0.03) Step 2 5.0 5.04.9 (0.06) (0.06) (0.04) Plasma Insulin Step 1 54.4 43.8 53.1 (mU/I)(4.4) (5.9) (4.6) Step 2 97.9 98.4 107.4 (5.3) (12.6) (7.2) MCR-I Step 115.0 17.0 14.9 (1.3) (1.6) (1.4) Step 2 14.6 14.5 12.8 (0.9) (0.9) (1.0)m-value Step 1 3.0 2.6 3.1 (mg/kg/min) (0.4) (0.3) (0.5) Step 2 7.9 7.0*7.8 (0.6) (0.9) (0.7) Glucose Rd Baseline 9.5 10.1 9.6 (1.1) (0.6) (0.8)Step 1 21.2 18.2 21.7 (2.5) (1.9) (3.2) Step 2 48.5 40.6* 46.7 (4.2)(4.6) (5.8) Glucose Ra Baseline 9.6 9.8 8.5 (1.6) (0.8) (1.3) Step 1 4.13.6 2.6 (0.9) (0.6) (0.9) Step 2 2.8 2.1 2.1 (1.8) (0.7) (2.3) GlycerolRa Baseline 5.2 3.7 4.0 (n = 5) (0.9) (0.4) (0.3) Step 1 2.1 2.6 1.5(0.2) (0.3) (0.2) Step 2 1.7 2.5 1.1* (0.3) (0.6) (0.1)

TABLE 4 5 mg 10 mg Combined Mean +/− SEM Baseline Treatment TreatmentTreatment Fasting IGF-1 (ng/ml) 214.15 +/− 22.3 207.10 +/− 34.9 144.24+/− 26.19 175.67 +/− 22.69 Overnight TBG (mmol/l)  5.27 +/− 0.07  5.01+/− 0.04  5.58 +/− 0.09  5.29 +/− 0.04 Overnight Inuslin  0.35 +/− 0.04 0.24 +/− 0.01  0.25 +/− 0.02  0.25 +/− 0.01 Requirement (mU/Kg/min)Overnight Plasma Insulin  16.48 +/− 1.1  19.24 +/− 1.1  14.45 +/− 1.1 16.67 +/− 1.1 (mU/I)

CONCLUSIONS

Specific GH blockade reduced IGF-I levels and overnight insulinrequirements. It did not affect insulin sensitivity the next morning,possibly because of the timing of the clamp or contracting effects ofreductions in GH action and IGF-1 on insulin sensitivity. Insulinrequirements were reduced by around 31%.

1-5. (canceled)
 6. A method of reducing overnight insulin requirement ofa patient suffering from Type 1 diabetes mellitus comprisingadministering insulin and the growth hormone (GH) antagonist pegvisomantto a patient suffering therefrom during the evening.
 7. A methodaccording to claim 6 comprising administering to the patient a dailydose of the GH antagonist pegvisomant and less frequent overnightinfusions of insulin together with a hyperinsulinaemic euglycaemicclamp.
 8. A method according to claim 7 wherein said overnight insulininfusions are administered at approximately three-weekly intervals. 9.(canceled)
 10. A method according to claim 6 rein each daily dose ofpegvisomant is from 1 to 20 mg.
 11. A method according to claim 10wherein each daily dose of pegvisomant is from 5 mg to 10 mg. 12.(canceled)
 13. A method of treating a patient suffering from both Type 1diabetes mellitus and from dawn phenomenon comprising administeringinsulin and the growth hormone (GH) antagonist pegvisomant to a patient.